US20080221110A1 - Compounds - Google Patents

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US20080221110A1
US20080221110A1 US11/550,005 US55000506A US2008221110A1 US 20080221110 A1 US20080221110 A1 US 20080221110A1 US 55000506 A US55000506 A US 55000506A US 2008221110 A1 US2008221110 A1 US 2008221110A1
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Prior art keywords
dihydro
methyl
mmol
methanol
pyrrolo
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Inventor
Nathalie Cailleau
David Thomas Davies
Joel Michael Esken
Alan Joseph Hennessy
Senthil Kumar Kusalakumari Sukumar
Roger Edward Markwell
Timothy James Miles
Neil David Pearson
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Glaxo Group Ltd
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Glaxo Group Ltd
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Priority to US11/550,005 priority Critical patent/US20080221110A1/en
Assigned to GLAXO GROUP LIMITED reassignment GLAXO GROUP LIMITED ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HENNESSY, ALAN JOSEPH, CAILLEAU, NATHALIE, DAVIES, DAVID THOMAS, ESKEN, JOEL MICHAEL, KUSALAKUMARI SUKUMAR, SENTIL KUMAR, MARKWELL, ROGER EDWARD, MILES, TIMOTHY JAMES, PEARSON, NEIL DAVID
Publication of US20080221110A1 publication Critical patent/US20080221110A1/en
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/06—Peri-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • This invention relates to novel compounds, compositions containing them and their use as antibacterials.
  • WO02/08224 WO02/50061, WO02/56882, WO02/96907, WO2003087098, WO2003010138, WO2003064421, WO2003064431, WO2004002992, WO2004002490, WO2004014361, WO2004041210, WO2004096982, WO2002050036, WO2004058144, WO2004087145, WO2006002047, WO2006014580, WO2006010040, WO2006017326, WO2006012396, WO2006017468, WO2006020561, WO2006081179, WO2006081264, WO2006081289, WO2006081178, WO2006081182, WO01/25227, WO02/40474, WO02/07572, WO2004024712, WO2004024713, WO2004035569, WO2004087647, WO2004089947, WO20050169
  • This invention provides a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof:
  • R 1a and R 1b are independently selected from hydrogen; halogen; cyano; (C 1-6 )alkyl; (C 1-6 )alkylthio; trifluoromethyl; trifluoromethoxy; carboxy; hydroxy optionally substituted with (C 1-6 )alkyl or (C 1-6 )alkoxy-substituted(C 1-6 )alkyl; (C 1-6 )alkoxy-substituted(C 1-6 )alkyl; hydroxy(C 1-6 )alkyl; an amino group optionally N-substituted by one or two (C 1-6 )alkyl, formyl, (C 1-6 )alkylcarbonyl or (C 1-6 )alkylsulphonyl groups; or aminocarbonyl wherein the amino group is optionally substituted by (C 1-4 )alkyl; R 2 is hydrogen, or (C 1-4 )alkyl, or together with R 6 forms Y as defined below; A is
  • R 3 is as defined for R 1a or R 1b or is oxo and n is 1 or 2: or A is a group (ii)
  • W 1 , W 2 and W 3 are CR 4 R 8
  • W 2 and W 3 are CR 4 R 8 and W 1 represents a bond between W 3 and N.
  • X is O, CR 4 R 8 , or NR 6 ;
  • R 4 is as defined for R 1a and R 1b and the remainder and R 8 are hydrogen or one R 4 and R 8 are together oxo and the remainder are hydrogen;
  • R 6 is hydrogen or (C 1-6 )alkyl; or together with R 2 forms Y;
  • R 7 is hydrogen; halogen; hydroxy optionally substituted with (C 1-6 )alkyl; or (C 1-6 )alkyl;
  • Y is CR 4 R 8 CH 2 ; CH 2 CR 4 R 8 ; (C ⁇ O); CR 4 R 8 ; CR 4 R 8 (C ⁇ O); or (C ⁇ O)CR 4 R 8 ;
  • U is selected from CO, and CH 2 and R 5 is an optionally substituted bicyclic carbocyclic or heterocyclic ring system (B):
  • X 1 is C or N when part of an aromatic ring, or CR 14 when part of a non-aromatic ring;
  • X 2 is N, NR 13 , O, S(O) x , CO or CR 14 when part of an aromatic or non-aromatic ring or may in addition be CR 14 R 15 when part of a non aromatic ring;
  • X 3 and X 5 are independently N or C;
  • Y 1 is a 0 to 4 atom linker group each atom of which is independently selected from N, NR 13 , O, S(O) x , CO and CR 14 when part of an aromatic or non-aromatic ring or may additionally be CR 14 R 15 when part of a non aromatic ring;
  • Y 2 is a 2 to 6 atom linker group, each atom of Y 2 being independently selected from N, NR 13 , O, S(O) x , CO, CR 14 when part of an aromatic or non-aromatic ring or may additionally be CR 14 R 15 when part of a non aromatic ring;
  • each of R 14 and R 15 is independently selected from: H; (C 1-4 )alkylthio; halo; carboxy(C 1-4 )alkyl; (C 1-4 )alkyl; (C 1-4 )alkoxycarbonyl; (C 1-4 )alkylcarbonyl; (C 1-4 )alkoxy (C 1-4 )alkyl; hydroxy; hydroxy(C 1-4 )alkyl; (C 1-4 )alkoxy; nitro; cyano; carboxy; amino or aminocarbonyl optionally mono- or di-substituted by (C 1-4 )alkyl; or
  • R 14 and R 15 may together represent oxo
  • each R 13 is independently H; trifluoromethyl; (C 1-4 )alkyl optionally substituted by hydroxy, (C 1-6 )alkoxy, (C 1-6 )alkylthio, halo or trifluoromethyl; (C 2-4 )alkenyl; (C 1-4 )alkoxycarbonyl; (C 1-4 )alkylcarbonyl; (C 1-6 )alkylsulphonyl; aminocarbonyl wherein the amino group is optionally mono or disubstituted by (C 1-4 )alkyl;
  • each x is independently 0, 1 or 2;
  • R 9 is hydrogen or hydroxy.
  • This invention also provides a method of treatment of bacterial infections in mammals, particularly in man, which method comprises the administration to a mammal in need of such treatment an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof.
  • the invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, in the manufacture of a medicament for use in the treatment of bacterial infections in mammals.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, and a pharmaceutically acceptable carrier.
  • each R 1a and R 1b is independently hydrogen, (C 1-4 )alkoxy, (C 1-4 )alkylthio, (C 1-4 )alkyl, cyano, carboxy, hydroxymethyl or halogen; more particularly hydrogen, methoxy, methyl, cyano, or halogen.
  • each R 1a and R 1b is hydrogen, methoxy, methyl, or halogen, such as chloro or fluoro. In some embodiments only one group R 1a or R 1b is other than hydrogen. In particular embodiments R 1a is methoxy, fluoro or cyano and R 1b is hydrogen, more particularly R 1a is fluoro and R 1b is hydrogen.
  • R 2 is hydrogen
  • R 9 is hydrogen
  • R 3 include hydrogen; optionally substituted hydroxy; optionally substituted amino; halogen; (C 1-4 ) alkyl; 1-hydroxy-(C 1-4 ) alkyl; optionally substituted aminocarbonyl. More particular R 3 groups are hydrogen; CONH 2 ; 1-hydroxyalkyl e.g. CH 2 OH; optionally substituted hydroxy e.g. methoxy; optionally substituted amino; and halogen, in particular fluoro. Most particularly R 3 is hydrogen, hydroxy or fluoro.
  • n is 1.
  • R 3 is in the 3- or 4-position.
  • A is (ia), n is 1 and R 3 is in the 3-position, and more particularly is cis to the NR 2 group.
  • A is a group (ia) in which n is 1 and R 3 is hydrogen or hydroxy.
  • X is CR 4 R 8 and R 8 is H or OH and more particularly OH is trans to R 7 .
  • WI is a bond.
  • R 7 is H.
  • W 1 is a bond
  • X, W 2 and W 3 are each CH 2 and R 7 is H.
  • U is CH 2 .
  • R 5 is an aromatic heterocyclic ring (B) having 8-11 ring atoms including 2-4 heteroatoms of which at least one is N or NR 13 in which, in particular embodiments, Y 2 contains 2-3 heteroatoms, one of which is 5 and 1-2 are N, with one N bonded to X 3 .
  • the heterocyclic ring (B) has ring (a) aromatic selected from optionally substituted benzo, pyrido and pyridazino and ring (b) non aromatic and Y 2 has 3-5 atoms, more particularly 4 atoms, including at least one heteroatom, with O, S, CH 2 or NR 13 bonded to X 5 where R 13 is other than hydrogen, and either NHCO bonded via N to X 3 , or O, S, CH 2 or NH bonded to X 3 .
  • the ring (a) contains aromatic nitrogen, and more particularly ring (a) is pyridine or pyrazine.
  • rings (B) include optionally substituted
  • R 13 is H if in ring (a) or in addition (C 1-4 )alkyl such as methyl or isopropyl when in ring (b). More particularly, in ring (b) R 13 is H when NR 13 is bonded to X 3 and (C 1-4 )alkyl when NR 13 is bonded to X 5 .
  • R 14 and R 15 are independently selected from hydrogen, halo, hydroxy, (C 1-4 ) alkyl, (C 1-4 )alkoxy, nitro and cyano. More particularly R 15 is hydrogen.
  • each R 14 is selected from hydrogen, chloro, fluoro, hydroxy, methyl, methoxy, nitro and cyano. Still more particularly R 14 is selected from hydrogen, fluorine or nitro.
  • R 14 and R 15 are each H.
  • R 5 include:
  • alkyl includes groups having straight and branched chains, for instance, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, pentyl and hexyl.
  • alkenyl should be interpreted accordingly.
  • Halo or halogen includes fluoro, chloro, bromo and iodo.
  • Haloalkyl moieties include 1-3 halogen atoms.
  • Some of the compounds of this invention may be crystallised or recrystallised from solvents such as aqueous and organic solvents. In such cases solvates may be formed.
  • This invention includes within its scope stoichiometric solvates including hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation.
  • phrases such as “a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof” are intended to encompass the compound of formula (I), a pharmaceutically acceptable salt of the compound of formula (I), a solvate of formula (I), or any pharmaceutically acceptable combination of these.
  • a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof may include a pharmaceutically acceptable salt of a compound of formula (I) that is further present as a solvate.
  • the compounds of formula (I) are intended for use in pharmaceutical compositions it will readily be understood that in particular embodiments they are provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and particularly at least 85%, especially at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions; these less pure preparations of the compounds should contain at least 1%, more suitably at least 5% and more particularly from 10 to 59% of a compound of the formula (I) or pharmaceutically acceptable salt and/or solvate thereof.
  • Particular compounds according to the invention include those mentioned in the examples and their pharmaceutically acceptable salts and solvates.
  • Pharmaceutically acceptable salts of the above-mentioned compounds of formula (I) include the acid addition or quaternary ammonium salts, for example their salts with mineral acids e.g. hydrochloric, hydrobromic, sulphuric nitric or phosphoric acids, or organic acids, e.g. acetic, fumaric ((2E)-2-butenedioic), succinic, maleic, citric, benzoic, p-toluenesulphonic (4-methylbenzene sulphonic), methanesulphonic, naphthalenesulphonic acid or tartaric acids.
  • mineral acids e.g. hydrochloric, hydrobromic, sulphuric nitric or phosphoric acids
  • organic acids e.g. acetic, fumaric ((2E)-2-butenedioic)
  • succinic maleic, citric, benzoic
  • p-toluenesulphonic (4-methylbenzene
  • Certain of the compounds of formula (I) may exist in the form of optical isomers, e.g. diastereoisomers and mixtures of isomers in all ratios, e.g. racemic mixtures.
  • the invention includes all such forms, in particular the pure isomeric forms.
  • the invention includes enantiomers and diastereoisomers at the attachment points of NR 2 , R 3 and/or R 9 .
  • the different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses.
  • R 21 is (C 1-16 )alkyl such as methyl
  • R 20 is UR 5 or a group convertible thereto
  • R 2′ is R 2 or a group convertible thereto
  • A, R 1a , R 1b , R 2 , U and R 5 are as defined in formula (I), to give a compound of formula (IIB):
  • R 9 is H, and thereafter optionally or as necessary converting R 20 and R 2′ to UR 5 and R 2 , interconverting any variable groups, and/or forming a pharmaceutically acceptable salt and/or solvate thereof.
  • the cyclisation reaction is effected by treatment of the compound of formula (IIA) with an activating agent such as methanesulphonyl chloride, p-toluenesulphonyl chloride, methanesulfonic anhydride or p-toluene sulfonic anhydride and an organic base such as triethylamine or diisopropylethylamine.
  • an activating agent such as methanesulphonyl chloride, p-toluenesulphonyl chloride, methanesulfonic anhydride or p-toluene sulfonic anhydride and an organic base such as triethylamine or diisopropylethylamine.
  • Mesylate or tosylate preparation takes place under standard conditions and the compound of formula (IIB) forms in situ.
  • R 21 is (C 1-6 )alkyl such as methyl
  • R 22 is H or (C 1-6 )alkyl such as methyl
  • R 1a , R 1b are as defined in formula (I):
  • the cyclisation reaction may be effected by treatment of the compound of formula (IIC) with lithium perchlorate in acetonitrile or lithium hydroxide in water to give the tricyclic hydroxy-carboxylic acid (IID).
  • Conversion of —CO 2 H to —CH 2 -A-NR 2 —UR 5 may be effected by methylation using methanol in sulphuric acid, followed by reduction to the diol with sodium borohydride in methanol, and conversion to the tosyl derivative with tosyl chloride/dibutyltin oxide.
  • R 20 and R 2′ is an N-protecting group, such as such as t-butoxycarbonyl, benzyloxycarbonyl or 9-fluorenylmethyloxycarbonyl.
  • N-protecting group such as such as t-butoxycarbonyl, benzyloxycarbonyl or 9-fluorenylmethyloxycarbonyl.
  • This may be removed by several methods well known to those skilled in the art (for examples see “ Protective Groups in Organic Synthesis , T. W. Greene and P. G. M. Wuts, Wiley-Interscience, 1999), for example conventional acid hydrolysis with, for example trifluoroacetic acid or hydrochloric acid.
  • the invention further provides compounds of formula (IIB) in which R 20 is hydrogen.
  • the free amine of formula (IIB) in which R 20 is hydrogen may be converted to NR 2 UR 5 by conventional means such as amide or sulphonamide formation with an acyl derivative R 5 COW or R 5 SO 2 W, for compounds where U is CO or SO 2 or, where U is CH 2 , by alkylation with an alkyl halide R 5 CH 2 -halide in the presence of base, acylation/reduction with an acyl derivative R 5 COW or reductive alkylation with an aldehyde R 5 CHO under conventional conditions (see for examples Smith, M. B.; March, J. M. Advanced Organic Chemistry , Wiley-Interscience).
  • the appropriate reagents containing the required R 5 group are known compounds or may be prepared analogously to known compounds, see for example WO02/08224, WO02/50061, WO02/56882, WO02/96907, WO2003087098, WO2003010138, WO2003064421, WO2003064431, WO2004002992, WO2004002490, WO2004014361, WO2004041210, WO2004096982, WO2002050036, WO2004058144, WO2004087145, WO06002047, WO06014580, WO06010040, WO06017326, WO06012396, WO06017468, WO06020561 and EP0559285.
  • R 5 contains an NH group
  • this may be protected with a suitable N-protecting group such as t-butoxycarbonyl, benzyloxycarbonyl or 9-fluorenylmethyloxycarbonyl during the coupling of the R 5 derivative with the free amine of formula (IIB).
  • the protecting group may be removed by conventional methods, such as by treatment with trifluoroacetic acid.
  • Compounds of general structure (III) may be prepared by reaction of acrylate ester (IV) with a compound HA-N(R 20 )R 2′ , such as a Boc protected amino-piperidine, under conventional conditions for Michael additions (see for examples Smith, M. B.; March, J. M. Advanced Organic Chemistry , Wiley-Interscience). Reduction of (III) to (IIA) occurs upon treatment with lithium aluminium hydride under conventional conditions (see for examples Smith, M. B.; March, J. M. Advanced Organic Chemistry , Wiley-Interscience).
  • the compound of formula (IIC) may be prepared by conventional epoxidation of the vinyl ester (IV) e.g. by oxidation with m-chloroperbenzoic acid or t-butyl hydrogen peroxide.
  • the aniline (XI) is converted to the cinnamide (X), which is cyclised with aluminium chloride (with loss of the phenyl moiety—See M. C. Elliot et al. S. R. Inglis et al. J. Med. Chem. 47 (22), 5405-5417 (2004)] Synlett, 5, 898-900 (2004)) to give (IX).
  • This is selectively O-alkylated with e.g. methyl iodide or dimethylsulphate to give (VIII) and the methyl group functionalised with N-bromosuccinimide to give the bromomethyl analogue (VII).
  • Quinolinone (XIV) may be prepared by reaction of commercially available aniline (XVI) with cinnamoyl chloride to give (XV) and its subsequent cyclisation (for an example of this procedure see Cottet, F.; Marull, M.; Lefebvre, O.; Schlosser, M European Journal of Organic Chemistry (2003), 8, 1559). (XIV) can be converted into the bromo-quinoline (XIII) under standard conditions (see for examples Smith, M. B.; March, J. M. Advanced Organic Chemistry , Wiley-Interscience).
  • the boronic acid (XII) can be synthesised from (XIII) under standard conditions (for an example see Li, W.; Nelson, D.; Jensen, M.; Hoerrner, R.; Cai, D.; Larsen, R.; Reider, P J. Org. Chem . (2002), 67(15), 5394).
  • the coupling of (XII) with the known bromo-acrylate, (for synthesis see Rachon, J.; Goedken, V.; Walborsky, H. J. Org. Chem . (1989), 54(5), 1006) to give (IV) may be accomplished using a Suzuki coupling reaction (for conditions see Littke, A.; Dai, C.; Fu, G. J. Am. Chem. Soc . (2000), 122(17), 4020 This route is particularly suitable for R 1a ⁇ H.
  • the RCOCl reagent in the first stage, cinnamoyl chloride may be replaced by (2E)-3-ethyloxy-2-propenoyl chloride and the subsequent cyclisation effected with trifluoroacetic acid or sulfuric acid instead of aluminium trichloride (E. Baston et al, European J. Med. Chem., 2000 35(10), 931.
  • R 1a and R 1b are as described in formula (I), with a compound R 5 CH 2 NH 2 , by reductive alkylation.
  • the diol 3 may be subjected to an enzymatic desymmetrization reaction to generate the desired E1 enantiomer of compound 4, by treatment with lipase TL and a vinyl ester (such as vinyl acetate or vinyl pivalate), followed by cyclisation with methanesulphonic anhydride, ester hydrolysis with sodium methoxide in methanol and activation of the resultant alcohol to mesylate 4 by conventional methods.
  • a vinyl ester such as vinyl acetate or vinyl pivalate
  • R 1a , R 1b , R 2 , A and R 5 are conventional.
  • suitable conventional hydroxy protecting groups which may be removed without disrupting the remainder of the molecule include acyl and alkylsilyl groups. N-protecting groups are removed by conventional methods.
  • R 1a and R 1b groups may be carried out conventionally, on compounds of formula (I) or (IIB).
  • R 1a or R 1b methoxy is convertible to R 1a or R 1b hydroxy by treatment with lithium and diphenylphosphine (general method described in Ireland et al, J. Amer. Chem. Soc., 1973, 7829) or HBr.
  • Alkylation of the hydroxy group with a suitable alkyl derivative bearing a leaving group such as halide yields R 1a or R 1b substituted alkoxy.
  • R 1a halogen is convertible to other R 1a by conventional means, for example to hydroxy, alkylthiol (via thiol) and amino using metal catalysed coupling reactions, for example using copper as reviewed in Synlett (2003), 15, 2428-2439 and Angewandte Chemie, International Edition, 2003, 42(44), 5400-5449.
  • R 1b halo such as bromo may be introduced by the method of M. A. Alonso et al, Tetrahedron 2003, 59(16), 2821.
  • R 1a or R 1b halo such as bromo may be converted to cyano by treatment with copper (I) cyanide in N,N-dimethylformamide.
  • R 1a or R 1b carboxy may be obtained by conventional hydrolysis of R 1a or R 1b cyano, and the carboxy converted to hydroxymethyl by conventional reduction.
  • HA-N(R 20 )R 2′ and (V) are known compounds or may be prepared analogously to known compounds, see for example WO2004/035569, WO2004/089947, WO02/08224, WO02/50061, WO02/56882, WO02/96907, WO2003087098, WO2003010138, WO2003064421, WO2003064431, WO2004002992, WO2004002490, WO2004014361, WO2004041210, WO2004096982, WO2002050036, WO2004058144, WO2004087145, WO2003082835, WO2002026723, WO06002047 and WO06014580.
  • the hydroxy-aminomethylpyrrolidines of formula (XIII) (HA-NH(R 20 ), A is (ii), X is CR 4 R 8 , W 1 is a bond, W 2 and W 3 are both CH 2 , R 4 and R 7 are H and R 8 is OH) can be prepared from doubly protected chiral intermediate (XVI), separated by preparative HPLC.
  • the benzyloxycarbonyl protecting group is removed by hydrogenation to give (XV) and the amino function converted to a trifluoroacetamide (XIV).
  • the t-butoxycarbonyl (Boc) protecting group is removed with HCl to give the pyrrolidine hydrochloride salt (III).
  • the intermediate (XVI) may be prepared by the general method of Scheme 7:
  • aminomethylpyrrolidine of formula (XVII) (HA-NH(R 20 ), A is (ii), X is CR 4 R 8 , W 1 is a bond, W 2 and W 3 are both CH 2 , R 4 , R 7 and R 8 are all H) can be prepared from commercially available Boc-protected aminomethylpyrrolidine, and converted to the trifluoroacetamide.
  • the aminomethylmorpholine intermediate of formula (XXI) (HA-NH(R 20 ), A is (ii), X is O, W 1 , W 2 and W 3 are each CH 2 ) may be prepared from a chiral dichlorobenzyl intermediate (XXIII) (WO2003082835) (Scheme 9) by first protecting the amino function with a Boc-protecting group (XXII), removing the dichlorobenzyl group by hydrogenation to give (XXI), protecting the morpholine N-atom with a benzyloxycarbonyl group (to allow purification by chromatography) (XX), and hydrogenation to afford the required morpholine derivative (XXI).
  • antibacterial compounds according to the invention may be formulated for administration in any convenient way for use in human or veterinary medicine, by analogy with other antibacterials.
  • compositions of the invention include those in a form adapted for oral, topical or parenteral use and may be used for the treatment of bacterial infection in mammals including humans.
  • compositions may be formulated for administration by any route.
  • the compositions may be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
  • topical formulations of the present invention may be presented as, for instance, ointments, creams or lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams.
  • the formulations may also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions.
  • suitable conventional carriers such as cream or ointment bases and ethanol or oleyl alcohol for lotions.
  • Such carriers may be present as from about 1% up to about 98% of the formulation. More usually they will form up to about 80% of the formulation.
  • Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.
  • suspending agents for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or
  • Suppositories will contain conventional suppository bases, e.g. cocoa-butter or other glyceride.
  • fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, water being preferred.
  • the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
  • the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
  • agents such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • the dry lyophilized powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use.
  • Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration.
  • the compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • compositions may contain from 0.1% by weight, preferably from 10-60% by weight, of the active material, depending on the method of administration. Where the compositions comprise dosage units, each unit will preferably contain from 50-1000 mg of the active ingredient.
  • the dosage as employed for adult human treatment will preferably range from 100 to 3000 mg per day, for instance 1500 mg per day depending on the route and frequency of administration. Such a dosage corresponds to 1.5 to 50 mg/kg per day. Suitably the dosage is from 5 to 30 mg/kg per day.
  • the compound of formula (I) may be the sole therapeutic agent in the compositions of the invention or a combination with other antibacterials If the other antibacterial is a ⁇ -lactam then a ⁇ -lactamase inhibitor may also be employed.
  • Compounds of formula (I) may be used in the treatment of bacterial infections caused by a wide range of organisms including both Gram-negative and Gram-positive organisms. Some compounds of formula (I) may be active against more than one organism. This may be determined by test methods described herein.
  • DMF refers to N,N-dimethylformamide
  • TFA refers to trifluoroacetic acid
  • THF refers to tetrahydrofuran
  • Pd/C palladium on carbon catalyst
  • DCM refers to dichloromethane
  • Boc refers to tert-Butoxycarbonyl
  • MeOH refers to methanol.
  • MP-carbonate refers to macroporous triethylammonium methylpolystyrene carbonate (Argonaut Technologies).
  • Chiralpak AD and AD-H columns comprise of silica for preparative columns (5 um particle size AD-H and 10 um particle size AD 21 ⁇ 250 mm; 20 um particle size AD, 101.1 ⁇ 250 mm) coated with Amylose tris(3,5-dimethylphenylcarbamate) (Chiral Technologies USA).
  • Chiralpak AS-H column comprise of amylose tris[(S)-alpha-methylbenzylcarbamate) coated onto 5 um silica.
  • Chiralpak IA column comprise of amylose tris(3,5-dimethylphenylcarbamate) immobilized onto 5 um silica.
  • Reactions involving metal hydrides including lithium hydride, lithium aluminium hydride, di-isobutylaluminium hydride, sodium hydride, sodium borohydride and sodium triacetoxyborohydride are carried out under argon.
  • DSC is conducted on a TA Instrument model Q100 Differential Scanning Calorimeter.
  • the sample is placed and weighed in a Al DSC pan.
  • the pan is sealed using the hand press supplied by the vendor.
  • the sample is ramped from 25° C. to 300° C. at 15° C./minute.
  • DSC is conducted on a TA instruments Q1000 Differential Scanning Calorimeter.
  • the sample is weighed and placed in the DSC pan (sample weights are recorded on the DSC plot).
  • the pan is sealed by applying pressure by hand and pushing each part the pan together (loose lid configuration).
  • the sample is ramped from 25° C. to 350° C. at 10° C./minute.
  • the sample is scanned using the following parameters:
  • Diffracted Beam optics Automatic slits (X'celerator module w/Alpha-1 Monochrometer), 0.04 radian soller slits
  • Method C PXRD PANalytical X'Pert Pro MPD w/Alpha-1 Monochrometer The sample is scanned using the following parameters:
  • Diffracted Beam optics fixed slits (X'celerator module), 0.04 radian soller slits
  • references to preparations carried out in a similar manner to, or by the general method of, other preparations may encompass variations in routine parameters such as time, temperature, workup conditions, minor changes in reagent amounts etc.
  • Racemic material (as trifluoroacetate salt; 114 g) was separated by preparative chiral hplc into the two enantiomers, E1 and E2, using a 20 um Chiralpak AD column, eluting with 80:20:0.1—CH 3 CN:CH 3 OH:Isopropylamine with Rt E1 7.2 min and Rt E2 8.3 min.
  • the recovery was E1 29.3 g (97.4% ee) and E2 30.2 g (94.4% ee).
  • Triethylamine can be substituted for isopropylamine in the preparative hplc stage.
  • the E1 enantiomer free base (63 mg) was prepared from 1-[(4-amino-1-piperidinyl)methyl]-9-fluoro-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (enantiomer EL) (64 mg) and 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carboxaldehyde (35 mg) by the general method of Example 1 (I) (chromatographed on silica gel, eluting with 0-20% methanol in dichloromethane), and exhibited the same NMR and MS spectroscopic properties.
  • Example 1 The material (racemic at the benzylic centre) was separated by preparative chiral hplc into the two diastereomers D1 and D2 in a similar manner to Example 1 (k).
  • the stationary phase was 5 um Chiralpak AD-H, eluting with 50:50:0.1—CH 3 CN:CH 3 OH:Isopropylamine, Rt D13.0 min and Rt D2 27 min.
  • the recovery was D1 222 mg (>99% de) and D2 123 mg (>99% de) from 400 mg of diasteromeric amine.
  • the residual trifluoroactetate salt was converted to the crude free base by stirring with an excess of MP-carbonate resin base until pH 7, filtering and evaporating to dryness. It was chromatographed on silica gel eluting with 10-40% 2M ammonia/methanol in dichloromethane, followed by further purification on a reverse-phase HPLC system with mass-directed collection (MDAP) (eluent acetonitrile/water/formic acid, monitoring for m/z 466), affording a white solid (35 mg, 62%).
  • MDAP mass-directed collection
  • Trimethylsilylacetylene (10 ml, 69 mmoles) and bis(triphenylphosphine)palladium(II) dichloride (0.645 g, 0.9 mmoles) were added and the mixture heated to 45° C. for 18 hrs. The mixture was then allowed to cool and filtered. The filtrate was evaporated to dryness and the residue partitioned between ethyl acetate and water. The organic layer was separated and dried (sodium sulphate).
  • Furo[2,3-c]pyridin-5-ylmethanol (1.29 g, 8.7 mmoles) was dissolved in ethanol (50 ml) and hydrogenated at S.T.P (standard temperature and pressure) over 10% palladium on charcoal paste for 18 hrs. The mixture was filtered through kieselguhr and the filtrate evaporated to dryness, to give (1.31 g, 100%).
  • Carbon monoxide was bubbled through a mixture of 3-chloro-6,7-dihydro[1,4]dioxino[2,3-c]pyridazine (100 mg, 0.58 mmol) and n-butanol (2.5 ml) for 10 minutes then palladium(II) chloride (5 mg, 0.03 mmol), 1,3-bis(diphenylphosphino)propane (24 mg, 0.06 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.1 ml, 0.64 mmol) were added. The mixture was heated at 100° C. for 5 hours under a stream of carbon monoxide, allowed to cool and then evaporated.
  • An alternative work-up procedure comprises quenching with methanol instead of with sodium hydroxide and DCM.
  • the reaction mixture is evaporated to dryness then dissolved in DCM and water added to form a gel-like precipitate.
  • Conc. HCl is added and the mixture stirred and then the phases partitioned and separated.
  • Salt is added to the aqueous phase followed by DCM, water and methanol. After stirring, the layers are separated, the aqueous extracted with DCM and all the combined organics dried over magnesium sulphate.
  • 3-Chloro-6,7-dihydro[1,4]dioxino[2,3-c]pyridazine may be converted to a morpholine amide by treatment with morpholine and CO, catalyzed by PdCl 2 and ligand (such as diphenylphosphinoferrocene) in a suitable solvent such as butyronitrile.
  • PdCl 2 and ligand such as diphenylphosphinoferrocene
  • a suitable solvent such as butyronitrile
  • the mixture was treated with aqueous sodium bicarbonate ( ⁇ 20 ml) and water (200 ml), cooled to 0° C., and the solid was collected by filtration, and dried in vacuo, to give the free base of the racemate as a solid (3.6 g; 69%).
  • Acetonitrile (10 mL) was added to crystalline 1-( ⁇ 4-[(6,7-dihydro[1,4]dioxino[2,3-c]pyridazin-3-ylmethyl)amino]-1-piperidinyl ⁇ methyl)-9-fluoro-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one enantiomer E1, free base 1 (458.0 mg).
  • benzoic acid 1.0 equivalent, 1.0 M solution in tetrahydrofuran
  • the slurry was stirred for 24 hours at room temperature.
  • the solids were then filtered and dried in a vacuum oven at 50° C. overnight to give about 512.5 mg title compound.
  • the fumaric acid may be dissolved in DMSO before addition, and if seed crystals are added to the solution of free base, these are preferably added immediately before the addition of fumaric acid.
  • Racemic material (as free base; 200 mg) was separated by preparative chiral hplc into the two enantiomers, E1 and E2, using a 5 um Chiralpak AD-H column, eluting with 50:50:0.1—CH 3 CN:CH 3 OH:Isopropylamine with Rt E1 7min and Rt E2 13.8 min.
  • the recovery was E1 80 mg (>99.5% pure) and E2 86 mg (>99.4% pure)
  • the E 1 enantiomer was converted into the dihydrochloride salt by dissolving the free base in a small amount of methanol and excess of a 6N solution of hydrochloric acid. The solution was then evaporated under vacuum to give a solid.
  • m-Chloroperbenzoic acid (50%; 6.95 g; 0.0201 mol) was added to a solution of a 1:1 mixture (5.251 g) of methyl 2-[7-fluoro-2-(methyloxy)-8-quinolinyl]-2-propenoate (2.63 g; 0.0101 mol) and methyl[7-fluoro-2-(methyloxy)-8-quinolinyl]acetate in dichloromethane (60 ml) and the mixture was heated at 50° C. for 6.5 hours and then 40° C. until 16 hours. [Further m-chloroperbenzoic acid (3.5 g) was added at 2 hours].
  • Racemic material (0.90 g) was separated by preparative chiral hplc into the two enantiomers, E1 and E2, using a Chiralpak AD 10 um (21 ⁇ 250 mm) column, eluting with 80:20:0.1—CH 3 CN:CH 3 OH:Isopropylamine (20 ml/min) with Rt E1 5.5 min and Rt E2 7.0 min.
  • the recovery was E1 379 mg (>99% ee) and E2 395 mg (>99% ee).
  • the title compound was prepared from 9-fluoro-1-(hydroxymethyl)-4-oxo-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl 4-methylbenzenesulfonate and 1,1-dimethylethyl (2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-4-piperidinylcarbamate (for a synthesis, see WO 2004058144 Example 99(h)) in a similar manner to procedures generally described herein.
  • the title compound was prepared from 9-fluoro-1-(hydroxymethyl)-4-oxo-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl 4-methylbenzenesulfonate and 1,1-dimethylethyl (2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-4-piperidinylcarbamate (for a synthesis, see WO 2004058144 Example 99(h)) followed by separation of the enantiomer E2 and preparation of the hydrochloride salt, in a similar manner to procedures generally described herein.
  • the residual trifluoroactetate salt was converted to the crude free base by dissolving in DCM:MeOH (1:1), stirring with an excess of MP-carbonate resin base until pH 7-8, filtering and evaporating to dryness to afford a clear oil (ca. 44 mg).
  • Ethyl 5-iodo-6-oxo-1,6-dihydro-3-pyridinecarboxylate (0.59 g, 2.01 mmol) (prepared according to the method of I. Houpis et al, Tet. Lett. 1994, 9355) with copper(I) iodide (20 mg, 0.105 mmol), potassium carbonate (0.55 g, 3.96 mmol), and 2-mercaptoethanol (1 ml, 14.3 mmol) in dry N,N-dimethylformamide (20 ml) was microwaved (150W) to reach a maximum internal temperature of 170° C., for 20 minutes. The reaction was cooled and combined with the reaction mixture from a second reaction carried out by identical means on the same scale.
  • Triphenylphosphine (0.796 g, 3.03 mmol) was added to a solution of diisopropyl azodicarboxylate (0.60 ml, 3.05 mmol) in tetrahydrofuran (75 ml) at 0° C. and stirred for 15 minutes.
  • Ethyl 5-[(2-hydroxyethyl)thio]-6-oxo-1,6-dihydro-3-pyridinecarboxylate 0.52 g, 2.14 mmol
  • the mixture was evaporated and the residue chromatographed on silica eluting with 0-100% ethyl acetate in hexane to give a white solid (0.25 g, 52%).
  • Ethyl 2,3-dihydro[1,4]oxathiino[2,3-b]pyridine-7-carboxylate (0.25 g, 1.11 mmol) in dry tetrahydrofuran was cooled in ice/water and treated with 1.0M diisobutylaluminium hydride in tetrahydrofuran (3.75 ml). The mixture was stirred overnight and further diisobutylaluminium hydride solution (2 ml) was added at 0° C. After 1 hour the mixture was treated with an aqueous solution of potassium sodium tartrate (25 ml), stirred for 1 hour and then evaporated.
  • the E2 enantiomer from Example 13 was converted into the dihydrochloride salt by dissolving the free base in a small amount of methanol and adding a 6N solution of hydrochloric acid. The solution was then evaporated under vacuum to give a solid.
  • the title compound was prepared from 9-fluoro-1-(hydroxymethyl)-4-oxo-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl 4-methylbenzenesulfonate and 1,1-dimethylethyl (2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-4-piperidinylcarbamate (for a synthesis, see WO 2004058144 Example 99(h)) followed by separation of the enantiomer E1, in a similar manner to procedures generally described herein.
  • reaction mixture was treated with water extracted 3 ⁇ with dichloromethane, dried (magnesium sulphate), evaporated and chromatographed on silica gel (100 g), eluting with 1:4 ethyl acetate-hexane to give the desired product (12.38 g, 93%).
  • Argon was bubbled through a mixture of 4-bromo-2- ⁇ [4-(methyloxy)phenyl]methyl ⁇ -6-( ⁇ [4-(methyloxy)phenyl]methyl ⁇ oxy)-3(2H)-pyridazinone and 5-bromo-2- ⁇ [4-(methyloxy)phenyl]methyl ⁇ -6-( ⁇ [4-(methyloxy)phenyl]methyl ⁇ oxy)-3(2H)-pyridazinone (1.35 g, 3.14 mmol) in dry dioxan (7.5 ml) for 20 minutes.
  • Butyl 3-(2- ⁇ [4-(methyloxy)phenyl]methyl ⁇ -3,6-dioxo-1,2,3,6-tetrahydro-4-pyridazinyl)propanoate (0.56 g, 1.56 mmol) was dissolved in dioxan and the solution evaporated to dryness, then redissolved in dry THF (30 ml). The solution, under argon, was cooled to ⁇ 30° C., and treated dropwise with a 1M solution of lithium aluminium hydride in THF (1.8 ml, 1.8 mmol), allowed to warm gradually to 0° C. and stirred in an ice bath for 30 minutes.
  • Butyl 3-(1- ⁇ [4-(methyloxy)phenyl]methyl ⁇ -3,6-dioxo-1,2,3,6-tetrahydro-4-pyridazinyl)propanoate (0.43 g, 1.19 mmol) was dissolved in dioxan and the solution evaporated to dryness, then redissolved in dry THF (20 ml). The solution under argon was cooled to ⁇ 30° C., treated dropwise with a 1M solution of lithium aluminium hydride in THF (1.4 ml, 1.4 mmol), allowed to warm gradually to 0° C. and stirred in an ice bath for 30 minutes.
  • the mixture was diluted with DCM and washed with sodium bicarbonate solution.
  • the aqueous was extracted with 10% methanol in DCM (3 ⁇ 80 ml).
  • the organic phase was dried and the solvent evaporated.
  • the residue was subjected to chromatography on silica gel using a 0-10% methanol-DCM gradient to provide the desired compound (1.47 g, 84%).
  • the acetate salt in DCM was converted to the dihydrochloride salt by adding an excess of 4M hydrogen chloride in dioxan, followed by evaporation to dryness, and trituration with ether to give a solid.
  • the acetate salt in DCM was converted to the dihydrochloride salt by adding an excess of 4M hydrogen chloride in dioxan, followed by evaporation to dryness, and trituration with ether to give a solid.
  • the acetate salt in DCM was converted to the dihydrochloride salt by adding an excess of 4M hydrogen chloride in dioxan, followed by evaporation to dryness, and trituration with ether to give a solid.
  • the acetate salt in DCM was converted to the dihydrochloride salt by adding an excess of 4M hydrogen chloride in dioxan, followed by evaporation to dryness, and trituration with ether to give a solid.
  • the acetate salt in DCM was converted to the dihydrochloride salt by adding an excess of 4M hydrogen chloride in dioxan, followed by evaporation to dryness, and trituration with ether to give a solid.
  • the acetate salt in DCM was converted to the dihydrochloride salt by adding an excess of 4M hydrogen chloride in dioxan, followed by evaporation to dryness, and trituration with ether to give a solid.
  • the acetate salt in DCM was converted to the dihydrochloride salt by adding an excess of 4M hydrogen chloride in dioxan, followed by evaporation to dryness, and trituration with ether to give a solid.
  • the reaction was heated at 70° C. for 24 hours and then treated with water and dichloromethane.
  • the aqueous fraction was re-extracted with dichloromethane.
  • the combined organic fractions were then dried (MgSO 4 ) and the solvent removed under reduced pressure.
  • the residue was subjected to chromatography on silica gel using a ethyl acetate-hexane gradient. This provided the desired compound as a yellow solid (381 mg, 63%).
  • This material was converted to the hydrochloride by dissolving in dichloromethane/methanol and adding 1 equivalent of 1M HCl/diethyl ether then evaporating to dryness.
  • This material was converted to the hydrochloride salt by dissolving in dichloromethane/methanol and adding 1 equivalent of 1M HCl/diethyl ether then evaporating to dryness.
  • This material was converted to the hydrochloride by dissolving in dichloromethane/methanol and adding 1 equivalent of 1M HCl/diethyl ether then evaporating to dryness.
  • This material was converted to the hydrochloride by dissolving in dichloromethane/methanol and adding 1 equivalent of 1M HCl/diethyl ether then evaporating to dryness.
  • the title compound was synthesised from the dihydrochloride salt of 1-[(4-amino-1-piperidinyl)methyl]-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one and 3,4-dihydro-2H-pyrano[2,3-c]pyridine-6-carbaldehyde (for a synthesis, see WO2004058144, Example 126(e)) according to the general method of Example 390), in 100% yield.
  • This material was converted to the hydrochloride by dissolving in dichloromethane/methanol and adding 1 equivalent of 1M HCl/diethyl ether then evaporating to dryness.
  • aqueous phase was further extracted twice with ethyl acetate and these extracts were combined, dried and evaporated (0.5 g).
  • the residues (3.7 g in total) were combined and chromatographed eluting with 0-15% methanol in ethyl acetate affording a white solid (2.7 g, 65%).
  • the free base of the title compound was prepared by preparative chiral hplc of the racemic material (slower-running enantiomer, see Example 47). This material was converted to the title compound with 1 equivalent of hydrochloric acid affording a solid (54 mg), >98% e.e.
  • the reaction was then filtered through kieselguhr, washing through with 1:1 MeOH/DCM. The solvents were evaporated and the residue partitioned between saturated aqueous NaHCO 3 and 20% MeOH in DCM. The aqueous was extracted twice more with 20% MeOH in DCM and then the combined organics were dried and evaporated. The residue was subjected to column chromatography on silica gel using a DCM, MeOH and aqueous ammonia gradient to provide the free base of the title compound (39 mg, 66%).
  • This material was converted to the dihydrochloride by dissolving in DCM and adding 1M HCl/diethyl ether then evaporating to dryness.
  • the reaction was then filtered through kieselguhr, washing through with 1:1 MeOH/DCM. The solvents were evaporated and the residue partitioned between saturated aqueous NaHCO 3 and 20% MeOH in DCM. The aqueous was extracted twice more with 20% MeOH in DCM and then the combined organics were dried and evaporated. The residue was subjected to column chromatography on silica gel using a DCM, MeOH and aqueous ammonia gradient to provide the free base of the title compound (32 mg, 55%).
  • This material was converted to the dihydrochloride by dissolving in DCM and adding 1M HCl/diethyl ether then evaporating to dryness.
  • Examples 56 and 57 1-( ⁇ 4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-piperidinyl ⁇ methyl)-9-(methyloxy)-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one, Enantiomers E1 and E2, Hydrochloride, and 1-( ⁇ 4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-piperidinyl ⁇ methyl)-9-(methyloxy)-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one, Enantiomer E1 Dihydrochloride
  • Each enantiomer was separately converted to the corresponding hydrochloride salt, by dissolving the free base in methanol and the appropriate amount of 6N HCl was added. The reaction was stirred for approximately 1 hour and the methanol was removed to leave the remaining mono HCl salts. Enantiomer E1 was also converted to the dihydrochloride salt.
  • This material was converted to the dihydrochloride salt by treating a solution in methanol (1 ml) with excess 1M hydrochloric acid in methanol (0.1 ml) followed by evaporation to dryness.

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US7732461B2 (en) 2006-04-26 2010-06-08 Glaxo Group Limited Tryclic nitrogen containing compounds and their use as antibacterials
US7732460B2 (en) 2005-12-22 2010-06-08 Glaxo Group Limited Heterocyclic compounds, their preparation and their use as antibacterials
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MX2011003370A (es) 2008-10-07 2011-04-28 Actelion Pharmaceuticals Ltd Compuestos antibioticos de oxazolidinona triciclicos.
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Citations (44)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3323868A (en) * 1961-12-14 1967-06-06 Laporte Chemical Manufacture of hydrogen peroxide
US3385881A (en) * 1962-06-23 1968-05-28 Hoechst Ag Process for the continuous preparation of monomeric and oligomeric bis-2-hydroxyethyl phthalates
US3917838A (en) * 1972-05-17 1975-11-04 Pfizer Control of plant diseases employing certain pyrrols compounds
US4066706A (en) * 1975-04-21 1978-01-03 Halcon International, Inc. Preparation of ethylbenzene hydroperoxide
US4269805A (en) * 1978-02-13 1981-05-26 Dynamit Nobel Aktiengesellschaft Reactor for the oxidation of alkyl aromatics with oxygen-containing gases in the liquid phase
US4317820A (en) * 1978-04-12 1982-03-02 Otsuka Pharmaceutical Co., Ltd. β-Lactam series compound and antibacterial pharmaceutical composition containing the same
US4399134A (en) * 1980-11-10 1983-08-16 Otsuka Pharmaceutical Co., Ltd. Pyrroloquinoline and benzoquinolizine compounds and antimicrobial compositions
US4416884A (en) * 1978-04-12 1983-11-22 Otsuka Pharmaceutical Co., Ltd. Piperazinylbenzoheterocyclic compounds
US4443447A (en) * 1982-10-25 1984-04-17 Riker Laboratories, Inc. Phenyl-substituted tricyclic antibacterial agents
US4550165A (en) * 1982-03-25 1985-10-29 Ciba Geigy Corporation Process for producing 1,2,5,6-tetrahydro-4H-pyrrolo-[3,2,1-ij]-quinolin-4-one
US4595755A (en) * 1982-03-25 1986-06-17 Ciba-Geigy Corporation 5-halo-1,2,3-(1,2-dihydropyrrolo)-4-quinolones
US4603199A (en) * 1982-10-25 1986-07-29 Riker Laboratories, Inc. Phenyl-substituted tricyclic antibacterial agent intermediates
US6136821A (en) * 1996-10-28 2000-10-24 Novartis Ag Naphthyridine derivatives
US6184388B1 (en) * 1995-11-22 2001-02-06 Daiichi Pharmaceutical Co., Ltd. Substituted aminocycloalkylpyrrolidine derivatives and cis-substituted aminocycloalkylpyrrolidine derivatives
US6289745B1 (en) * 1999-05-04 2001-09-18 James Bowers High temperature insertion type flow element and mounting extension
US6391865B1 (en) * 1999-05-04 2002-05-21 Schering Corporation Piperazine derivatives useful as CCR5 antagonists
US20030069252A1 (en) * 1999-05-04 2003-04-10 Baroudy Bahige M. Piperazine derivatives useful as CCR5 antagonists
US20040138219A1 (en) * 2001-01-22 2004-07-15 David Thomas Davies Quinolines and nitrogenated derivative therof substituted in 4-position by a piperidine-containing moiety and their use as antibacterial agents
US20040198755A1 (en) * 2001-05-25 2004-10-07 Dartois Catherine Genevieve Yvette Bicyclic nitrogen-containing heterocyclic derivatives for use as antibacterials
US20050085494A1 (en) * 2002-01-25 2005-04-21 Daines Robert A. Aminopiperidine compounds, process for their preparation, and pharmaceutical compositions containing them
US20050101588A1 (en) * 2003-09-22 2005-05-12 Grant Eugene B.Iii 7-Amino alkylidenyl-heterocyclic quinolones and naphthyridones
US20060041123A1 (en) * 2002-12-18 2006-02-23 Axten Jeffrey M Antibacterial agents
US20060052359A1 (en) * 2004-09-09 2006-03-09 Grant Eugene B 7-Amino alkylidenyl-heterocyclic quinolones and naphthyridones
US20060058287A1 (en) * 2002-06-26 2006-03-16 Axten Jeffrey M Compounds
US20060105964A1 (en) * 1999-05-04 2006-05-18 Schering Corporation Piperazine derivatives useful as CCR5 antagonists
US7196090B2 (en) * 2002-07-25 2007-03-27 Warner-Lambert Company Kinase inhibitors
US20070099903A1 (en) * 2005-10-21 2007-05-03 Mueller Stephan G Selected CGRP antagonists, processes for preparing them and their use as pharmaceutical compositions
US20070185153A1 (en) * 2005-12-22 2007-08-09 Nathalie Cailleau Compounds
US20070254872A1 (en) * 2004-07-08 2007-11-01 Glaxo Group Limited Antibacterial Agents
US20070287701A1 (en) * 2004-06-15 2007-12-13 Smithkline Beecham Corporation Antibacterial Agents
US20080280892A1 (en) * 2005-10-21 2008-11-13 Nathalie Cailleau Compounds
US20080280911A1 (en) * 2005-10-21 2008-11-13 Glaxo Group Limited Cinnoline Compounds as Inhibitors of Phosphodiesterase Type IV (Pde4)
US20090062265A1 (en) * 2006-04-06 2009-03-05 Graham Elgin Jones Pyrrolo-Quinoxalinone Derivatives as Antibacterials
US20090137568A1 (en) * 2006-04-26 2009-05-28 Glaxo Group Limited Tryclic Nitrogen Containing Compounds and their Use as Antibacterials
US20090198063A1 (en) * 2006-05-26 2009-08-06 Toyama Chemical Co., Ltd. Novel heterocyclic compound or salt thereof and intermediate thereof
US20090270374A1 (en) * 2006-07-20 2009-10-29 Llius Ballell Derivatives and analogs of n-ethylquinolones and n-ethylazaquinolones
US20100004230A1 (en) * 2006-07-03 2010-01-07 Glaxo Group Limited Azatricyclic compounds and their use
US20100048544A1 (en) * 2007-04-13 2010-02-25 Lluis Ballell-Pages Pyrrolo (3, 2, 1-ij) quinoline-4-one-derivatives for treating tuberculosis
US20100056502A1 (en) * 2007-03-23 2010-03-04 Glaxo Group Limited Compounds
US20100087424A1 (en) * 2007-04-20 2010-04-08 Glaxo Group Limited Tricyclic nitrogen containing heterocycles as antibacterial agents
US20100137353A1 (en) * 2007-04-20 2010-06-03 Glaxo Group Limited Tricyclic compounds as antibacterials
US20100137282A1 (en) * 2007-04-20 2010-06-03 David Evan Davies Tricyclic nitrogen containing compounds as antibacterial agents
US20100152441A1 (en) * 2005-06-16 2010-06-17 Astrazeneca Ab Compounds for the treatment of multi-drug resistant bacterial infections
US20100168418A1 (en) * 2005-06-24 2010-07-01 Toyama Chemical Co., Ltd. Novel nitrogenated heterocyclic compound and salt thereof

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH11222407A (ja) * 1997-11-14 1999-08-17 Sankyo Co Ltd 新規殺菌剤
UY27192A1 (es) * 2001-03-01 2002-09-30 Smithkline Beecham Corp Inhibidores de peptido-deformilasa

Patent Citations (59)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3323868A (en) * 1961-12-14 1967-06-06 Laporte Chemical Manufacture of hydrogen peroxide
US3385881A (en) * 1962-06-23 1968-05-28 Hoechst Ag Process for the continuous preparation of monomeric and oligomeric bis-2-hydroxyethyl phthalates
US3917838A (en) * 1972-05-17 1975-11-04 Pfizer Control of plant diseases employing certain pyrrols compounds
US4066706A (en) * 1975-04-21 1978-01-03 Halcon International, Inc. Preparation of ethylbenzene hydroperoxide
US4269805A (en) * 1978-02-13 1981-05-26 Dynamit Nobel Aktiengesellschaft Reactor for the oxidation of alkyl aromatics with oxygen-containing gases in the liquid phase
US4317820A (en) * 1978-04-12 1982-03-02 Otsuka Pharmaceutical Co., Ltd. β-Lactam series compound and antibacterial pharmaceutical composition containing the same
US4416884A (en) * 1978-04-12 1983-11-22 Otsuka Pharmaceutical Co., Ltd. Piperazinylbenzoheterocyclic compounds
US4399134A (en) * 1980-11-10 1983-08-16 Otsuka Pharmaceutical Co., Ltd. Pyrroloquinoline and benzoquinolizine compounds and antimicrobial compositions
US4552879A (en) * 1980-11-10 1985-11-12 Otsuka Pharmaceutical Co., Ltd. Benzoheterocyclic compounds and pharmaceutical composition thereof
US4595755A (en) * 1982-03-25 1986-06-17 Ciba-Geigy Corporation 5-halo-1,2,3-(1,2-dihydropyrrolo)-4-quinolones
US4550165A (en) * 1982-03-25 1985-10-29 Ciba Geigy Corporation Process for producing 1,2,5,6-tetrahydro-4H-pyrrolo-[3,2,1-ij]-quinolin-4-one
US4603199A (en) * 1982-10-25 1986-07-29 Riker Laboratories, Inc. Phenyl-substituted tricyclic antibacterial agent intermediates
US4443447A (en) * 1982-10-25 1984-04-17 Riker Laboratories, Inc. Phenyl-substituted tricyclic antibacterial agents
US6184388B1 (en) * 1995-11-22 2001-02-06 Daiichi Pharmaceutical Co., Ltd. Substituted aminocycloalkylpyrrolidine derivatives and cis-substituted aminocycloalkylpyrrolidine derivatives
US6136821A (en) * 1996-10-28 2000-10-24 Novartis Ag Naphthyridine derivatives
US6689765B2 (en) * 1999-05-04 2004-02-10 Schering Corporation Piperazine derivatives useful as CCR5 antagonists
US6391865B1 (en) * 1999-05-04 2002-05-21 Schering Corporation Piperazine derivatives useful as CCR5 antagonists
US20030069252A1 (en) * 1999-05-04 2003-04-10 Baroudy Bahige M. Piperazine derivatives useful as CCR5 antagonists
US20060105964A1 (en) * 1999-05-04 2006-05-18 Schering Corporation Piperazine derivatives useful as CCR5 antagonists
US20040067961A1 (en) * 1999-05-04 2004-04-08 Baroudy Bahige M. Piperazine derivatives useful as CCR5 antagonists
US20080188485A1 (en) * 1999-05-04 2008-08-07 Schering Corporation Piperidine derivatives useful as ccr5 antagonists
US7384944B2 (en) * 1999-05-04 2008-06-10 Schering Corporation Piperazine derivatives useful as CCR5 antagonists
US6289745B1 (en) * 1999-05-04 2001-09-18 James Bowers High temperature insertion type flow element and mounting extension
US20040138219A1 (en) * 2001-01-22 2004-07-15 David Thomas Davies Quinolines and nitrogenated derivative therof substituted in 4-position by a piperidine-containing moiety and their use as antibacterial agents
US7205408B2 (en) * 2001-01-22 2007-04-17 Smithkline Beecham, P.L.C. Quinolines and nitrogenated derivative thereof substituted in 4-position by a piperidine-containing moiety and their use as antibacterial agents
US7186730B2 (en) * 2001-05-25 2007-03-06 Smithkline Beecham P.L.C. Bicyclic nitrogen-containing heterocyclic derivatives for use as antibacterials
US20040198755A1 (en) * 2001-05-25 2004-10-07 Dartois Catherine Genevieve Yvette Bicyclic nitrogen-containing heterocyclic derivatives for use as antibacterials
US20050085494A1 (en) * 2002-01-25 2005-04-21 Daines Robert A. Aminopiperidine compounds, process for their preparation, and pharmaceutical compositions containing them
US7109213B2 (en) * 2002-01-29 2006-09-19 Glaxo Group Limited Aminopiperidine compounds, process for their preparation, and pharmaceutical compositions containing them
US7498326B2 (en) * 2002-06-26 2009-03-03 Glaxo Group Limited Compounds
US20060058287A1 (en) * 2002-06-26 2006-03-16 Axten Jeffrey M Compounds
US7196090B2 (en) * 2002-07-25 2007-03-27 Warner-Lambert Company Kinase inhibitors
US20060041123A1 (en) * 2002-12-18 2006-02-23 Axten Jeffrey M Antibacterial agents
US20050101588A1 (en) * 2003-09-22 2005-05-12 Grant Eugene B.Iii 7-Amino alkylidenyl-heterocyclic quinolones and naphthyridones
US7691850B2 (en) * 2004-06-15 2010-04-06 Glaxo Group Limited Antibacterial agents
US20070287701A1 (en) * 2004-06-15 2007-12-13 Smithkline Beecham Corporation Antibacterial Agents
US20070254872A1 (en) * 2004-07-08 2007-11-01 Glaxo Group Limited Antibacterial Agents
US20060052359A1 (en) * 2004-09-09 2006-03-09 Grant Eugene B 7-Amino alkylidenyl-heterocyclic quinolones and naphthyridones
US20100152441A1 (en) * 2005-06-16 2010-06-17 Astrazeneca Ab Compounds for the treatment of multi-drug resistant bacterial infections
US20100168418A1 (en) * 2005-06-24 2010-07-01 Toyama Chemical Co., Ltd. Novel nitrogenated heterocyclic compound and salt thereof
US20080280892A1 (en) * 2005-10-21 2008-11-13 Nathalie Cailleau Compounds
US20080280911A1 (en) * 2005-10-21 2008-11-13 Glaxo Group Limited Cinnoline Compounds as Inhibitors of Phosphodiesterase Type IV (Pde4)
US20070099903A1 (en) * 2005-10-21 2007-05-03 Mueller Stephan G Selected CGRP antagonists, processes for preparing them and their use as pharmaceutical compositions
US7625886B2 (en) * 2005-10-21 2009-12-01 Boehringer Ingelheim International Gmbh Selected CGRP antagonists, processes for preparing them and their use as pharmaceutical compositions
US20090036433A1 (en) * 2005-12-22 2009-02-05 Nathalie Caileau Heterocyclic Compounds, their Preparation and their Use as Antibacterials
US7732460B2 (en) * 2005-12-22 2010-06-08 Glaxo Group Limited Heterocyclic compounds, their preparation and their use as antibacterials
US20070185153A1 (en) * 2005-12-22 2007-08-09 Nathalie Cailleau Compounds
US7709483B2 (en) * 2006-04-06 2010-05-04 Glaxo Group Limited Pyrrolo-quinoxalinone derivatives as antibacterials
US20090062265A1 (en) * 2006-04-06 2009-03-05 Graham Elgin Jones Pyrrolo-Quinoxalinone Derivatives as Antibacterials
US7732461B2 (en) * 2006-04-26 2010-06-08 Glaxo Group Limited Tryclic nitrogen containing compounds and their use as antibacterials
US20090137568A1 (en) * 2006-04-26 2009-05-28 Glaxo Group Limited Tryclic Nitrogen Containing Compounds and their Use as Antibacterials
US20090198063A1 (en) * 2006-05-26 2009-08-06 Toyama Chemical Co., Ltd. Novel heterocyclic compound or salt thereof and intermediate thereof
US20100004230A1 (en) * 2006-07-03 2010-01-07 Glaxo Group Limited Azatricyclic compounds and their use
US20090270374A1 (en) * 2006-07-20 2009-10-29 Llius Ballell Derivatives and analogs of n-ethylquinolones and n-ethylazaquinolones
US20100056502A1 (en) * 2007-03-23 2010-03-04 Glaxo Group Limited Compounds
US20100048544A1 (en) * 2007-04-13 2010-02-25 Lluis Ballell-Pages Pyrrolo (3, 2, 1-ij) quinoline-4-one-derivatives for treating tuberculosis
US20100087424A1 (en) * 2007-04-20 2010-04-08 Glaxo Group Limited Tricyclic nitrogen containing heterocycles as antibacterial agents
US20100137353A1 (en) * 2007-04-20 2010-06-03 Glaxo Group Limited Tricyclic compounds as antibacterials
US20100137282A1 (en) * 2007-04-20 2010-06-03 David Evan Davies Tricyclic nitrogen containing compounds as antibacterial agents

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080280892A1 (en) * 2005-10-21 2008-11-13 Nathalie Cailleau Compounds
US7732460B2 (en) 2005-12-22 2010-06-08 Glaxo Group Limited Heterocyclic compounds, their preparation and their use as antibacterials
US7732461B2 (en) 2006-04-26 2010-06-08 Glaxo Group Limited Tryclic nitrogen containing compounds and their use as antibacterials
US20100137282A1 (en) * 2007-04-20 2010-06-03 David Evan Davies Tricyclic nitrogen containing compounds as antibacterial agents
US8389524B2 (en) 2007-04-20 2013-03-05 Glaxo Group Limited Tricyclic nitrogen containing compounds as antibacterial agents
WO2018159609A1 (ja) 2017-02-28 2018-09-07 三井化学アグロ株式会社 植物病害防除組成物およびそれを施用する植物病害の防除方法
KR20190110115A (ko) 2017-02-28 2019-09-27 미쓰이가가쿠 아그로 가부시키가이샤 식물 병해 방제 조성물 및 그것을 시용(施用)하는 식물 병해의 방제 방법
US11185076B2 (en) 2017-02-28 2021-11-30 Mitsui Chemicals Agro, Inc. Composition for controlling plant diseases and method for controlling plant diseases applying the same

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